Origin of fatigue in multiple sclerosis: review of the literature.

Fatigue is one of the most common and most disabling symptoms of multiple sclerosis (MS). Although numerous studies have tried to reveal it, no definite pathogenesis factor behind this fatigue has been identified. Fatigue may be directly related to the disease mechanisms (primary fatigue) or may be secondary to non-disease-specific factors. Primary fatigue may be the result of inflammation, demyelination, or axonal loss. A suggested functional cortical reorganization may result in a higher energy demand in certain brain areas, culminating in an increase of fatigue perception. Higher levels of some immune markers were found in patients with MS-related fatigue, whereas other studies rejected this hypothesis. There may be a disturbance in the neuroendocrine system related to fatigue, but it is not clear whether this is either the result of the interaction with immune activation or the trigger of this process. Fatigue may be secondary to sleep problems, which are frequently present in MS and in their turn result from urinary problems, spasms, pain, or anxiety. Pharmacologic treatment of MS (symptoms) may also provoke fatigue. The evidence for reduced activity as a cause of secondary fatigue in MS is inconsistent. Psychological functioning may at least play a role in the persistence of fatigue. Research did not reach consensus about the association of fatigue with clinical or demographic variables, such as age, gender, disability, type of MS, education level, and disease duration. In conclusion, it is more likely to explain fatigue from a multifactor perspective than to ascribe it to one mechanism. The current evidence on the pathogenesis of primary and secondary fatigue in MS is limited by inconsistency in defining specific aspects of the concept fatigue, by the lack of appropriate assessment tools, and by the use of heterogeneous samples. Future research should overcome these limitations and also include longitudinal designs.